This study has been transitioned to CTIS with ID 2023-504303-86-00 check the CTIS register for the current data. Primary objective:To evaluate the efficacy of atezolizumab plus bevacizumab compared with active surveillance on the basis of recurrence…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
carcinoma
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint:
1. RFS
Secondary outcome
Secundary endpoint
1. OS rate at 24 months and 36 months
2. OS
3. RFS as determined by the investigator
4. TTR
5. Time to EHS or macrovascular invasion
6. RFS after randomization as determined by the investigator and by an IRF,
among patients in the PD-L1-high subgroup
7. Incidence and severity of adverse events, with severity determined according
to NCI CTCAE v5.0
8. Change from baseline in targeted vital signs
9. Change from baseline in targeted clinical laboratory test results
10. Serum concentration of atezolizumab at specified timepoints
11. Prevalence of anti-drug antibody (ADAs) to atezolizumab at baseline and
incidence of ADAs to atezolizumab during the study
Background summary
Liver cancer is the fifth most common cancer, accounting for 7% of all cancers,
and the
second most frequent cause of cancer-related death globally, with 854,000 new
cases
and 810,000 deaths per year. Hepatocellular carcinoma (HCC) represents
approximately 90% of primary liver cancers and thus represents a significant
global
public health issue. On the basis of annual projections, the World Health
Organization
estimates that in excess of 1 million people will die from liver cancer in 2030
(Villanueva
2019).
The majority of HCCs occur in patients with underlying liver disease, mostly as
a result
of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or alcohol
abuse. HBV
infection accounts for the majority of HCC cases worldwide; however, in Western
countries and Japan, HCV is the main cause of HCC (Villanueva 2019). Universal
HBV
vaccination and wide implementation of direct-acting antiviral agents against
HCV are
likely to change the etiologic landscape of HCC. However, the incidence of
non-alcoholic fatty liver disease (NAFLD), which is a risk factor for HCC, is
increasing
worldwide and NAFLD will soon become a leading cause of liver cancer in Western
countries (Villanueva 2019).
Study objective
This study has been transitioned to CTIS with ID 2023-504303-86-00 check the CTIS register for the current data.
Primary objective:
To evaluate the efficacy of atezolizumab plus bevacizumab compared with active
surveillance on the basis of recurrence-free survival (RFS).
Secondary objectives:
1. To evaluate the efficacy of atezolizumab plus bevacizumab compared with
active surveillance on the basis of overall survival (OS), RFS after
randomization as determined by the investigator and by an Independent Review
Facility (IRF), time to recurrence (TTR), OS rate at 24 months and 36 months,
Time to extrahepatic spread or macrovascular invasion after randomization
2. To evaluate the safety of atezolizumab plus bevacizumab compared with active
surveillance
3. To characterize the PK profile of atezolizumab when given in combination
with bevacizumab
4. To evaluate the immune response to atezolizumab
Study design
This is a Phase III, global, multicenter, open-label, two-arm, randomized study
designed to evaluate the efficacy and safety of adjuvant therapy with
atezolizumab plus bevacizumab compared with active surveillance in patients
with completely resected or ablated HCC who are at high risk for disease
recurrence.Patients who have undergone surgical resection may have received 1
cycle of adjuvant TACE prior to study entry (randomization), if deemed
appropriate by the investigator and if consistent with local standards of care
(see Section 4.1.1 in the protocol for details).
The definition of high risk is based on composite criteria including size of
the largest tumor, number of tumors, and presence of either microvascular
invasion (defined as the presence of tumor emboli within the central vein, the
portal vein, or large capsular vessels) or poorly differentiated microscopic
appearance (histologic Grade 3 or 4). The criteria for high risk of HCC
recurrence used in this study are presented by type of curative treatment in
Table 2 in protocol.
Study burden and risks
There are several potentially curative or palliative approaches to the
treatment of HCC,
including surgical resection and ablation.
Liver resection provides an opportunity for long-term, cancer-free survival and
represents the primary curative treatment option for patients with HCC deemed
to be
surgical candidates. Eligibility for curative resection is typically based on
disease stage
as well as assessment of functional liver reserve; however, the concept of
"resectability"
varies significantly depending on local clinical practice and guidelines.
Local ablative strategies such as radiofrequency ablation (RFA) and microwave
ablation
(MWA) are potentially curative options typically offered to patients with very
early or
early stage HCC who are not candidates for resection (Villanueva 2019). As
compared
with resection, ablation has fewer complications but provides worse local
control for
larger tumors (Villanueva 2019).
Tumor recurrence is a major post-procedural complication associated with both
resection and ablation, with 50% to 70% of patients experiencing recurrence by
5 years
(Villanueva 2019). The risk of HCC recurrence after curative intervention is
primarily
related to the number of tumors and tumor characteristics at the time of
surgery or
ablation, such as size, degree of differentiation, and the presence of vascular
invasion.
For patients harboring one or more of these high-risk features (tumor size,
tumor number,
vascular invasion, poorly differentiated tumor), the prognosis following
curative
intervention is poor. In one study, 5-year disease-free survival rates
following resection
were 26% in patients with large/multinodular HCC and 18% in patients with
macrovascular invasion (Zhong et al. 2015). Five-year survival rates were 42% in
patients with large/multinodular HCC and 18% in patients with macrovascular
invasion.
In a retrospective analysis, 5-year recurrence-free survival (RFS) rates
following
resection were 13% versus 34% in patients with and without microvascular
invasion,
respectively (Shen et al. 2018). In addition, histologic tumor grade has been
shown to
influence survival after resection, with patients harboring poorly
differentiated tumors
having a worse prognosis compared with patients with moderately or
well-differentiated
tumors (Pawlik et al. 2005; Martins-Filho et al. 2017).
For patients with high-risk disease, effective and well-tolerated adjuvant
therapies are needed in order to prevent disease
recurrence and to increase cure rates.
Beneluxlaan 2a Beneluxlaan 2a
Woerden 3446 GR
NL
Beneluxlaan 2a Beneluxlaan 2a
Woerden 3446 GR
NL
Listed location countries
Age
Inclusion criteria
- For the 1st, 2nd, 5th, and 10th patients at each site: Medical Monitor
approval prior to randomization in order to monitor adherence to key
eligibility criteria
- Age >= 18 years
- Participants with a first diagnosis of HCC who have undergone either a
curative resection or ablation within 4-12 weeks of randomization (not
applicable for crossover)
- Documented diagnosis of HCC that has been completely resected or
ablated (not applicable for crossover).
- Absence of major macrovascular (gross vascular) invasion and of the
portal vein (Vp3 or Vp4) or any grade of macrovascular invasion in the
hepatic vein or inferior vena cava (not applicable for crossover)
Note: Patients undergoing resection with minor vascular invasion of the
portal vein (Vp1 or Vp2) as detected by either imaging or pathological
examination are allowed
- Absence of extrahepatic spread as confirmed by CT or MRI scan of the
chest abdomen, pelvis, and head prior to and following curative
procedure
- Full recovery from surgical resection or ablation within 4 weeks prior to
randomization
- High risk for HCC recurrence after resection or ablation
- For patients who received post-operative transarterial
chemoembolization: full recovery from the procedure within 4 weeks
prior to randomization
- For patients with resected HCC, availability of a representative
baseline tumor tissue sample
- Negative HIV test at screening
- Documented virology status of hepatitis, as confirmed by screening
hepatitis B virus (HBV) and hepatitis C virus (HCV) tests
- For patients with active HBV: HBV DNA < 500 IU/mL during
screening, initiation of anti-HBV treatment at least 14 days prior to
randomization and willingness to continue anti-HBV treatment during
the study
- For patients enrolled in the extended China enrollment phase: current
resident of mainland China and of Chinese ancestry
- Performance of an esophagogastroduodenoscopy either before
resection or ablation as part of pre-procedure work-up or during
screening, and assessment and treatment of varices of all sizes per local
standard of care prior to randomization
- Eastern Cooperative Oncology Group Performance Status of 0 or 1
- Child-Pugh Class A status
- Adequate hematologic and end-organ function
- For women of childbearing potential: agreement to remain abstinent
or use contraceptive methods and agreement to refrain from donating
eggs for 5 months after the final dose of atezolizumab and for 6 months after
the final dose of bevacizumab
- For men: agreement to remain abstinent or use a condom, and
agreement to refrain from donating sperm for during the treatment
period and for 6 months after the final dose of bevacizumab to avoid
exposing the embryo
Additional Inclusion Criteria for Crossover for Patients in Arm B
- Documentation of unequivocal recurrence as defined by European
Association for the Study of the Liver Clinical Practice Guidelines or
RECIST v1.1 criteria that is confirmed by the IRF
- For Arm B patients who undergo surgical resection or ablation for
first recurrence: full recovery from surgical resection or ablation within 4
weeks prior to Day 1 of Cycle 1
- Availability of a representative tumor specimen obtained at the time
of recurrence for exploratory biomarker research
- After recurrence assessments are performed by the investigator and
IRF, approval for crossover must be received from the Medical Monitor
Exclusion criteria
- Known fibrolamellar HCC, sarcomatoid HCC, or mixed
cholangiocarcinoma and HCC
- Recurrent HCC prior to randomization
- Evidence of residual, recurrent, or metastatic disease at
randomization (not applicable for crossover)
- Clinically significant ascites
- History of hepatic encephalopathy
- Prior bleeding event due to untreated or incompletely treated
esophageal and/or gastric varices within 6 months prior to
randomization
- Active or history of autoimmune disease or immune deficiency
- History of idiopathic pulmonary fibrosis, organizing pneumonia, druginduced
pneumonitis, or idiopathic pneumonitis, or evidence of active
pneumonitis on screening chest CT scan
- Significant cardiovascular disease (such as New York Heart
Association Class II or greater cardiac disease, myocardial infarction, or
cerebrovascular accident) within 3 months prior to Day 1 of Cycle 1,
unstable arrhythmia, or unstable angina
- History of malignancy other than HCC within 5 years prior to
screening, with the exception of malignancies with a negligible risk of
metastasis or death, such as adequately treated carcinoma in situ of the
cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal
carcinoma in situ, or Stage I uterine cancer
- Active tuberculosis
- Severe infection within 4 weeks prior to Day 1 of Cycle 1, including,
but not limited to, hospitalization for complications of infection,
bacteremia, or severe pneumonia, or any active infection that in the
opinion of the investigator, could impact patient safety
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior
to Day 1 of Cycle 1
- Prior allogeneic stem cell or solid organ transplantation
- On the waiting list for liver transplantation
- Any other disease, metabolic dysfunction, physical examination
finding, or clinical laboratory finding that contraindicates the use of an
investigational drug, may affect the interpretation of the results, or may
render the patient at high risk from treatment complications
- Pregnant or breastfeeding, or intending to become pregnant during
the study or within 5 months after the final dose of atezolizumab or
within 6 months after the final dose of bevacizumab
- Co-infection with HBV and HCV
- Co-infection with HBV and hepatitis D viral infection
- Clinically significant uncontrolled or symptomatic hypercalcemia
- History of severe allergic anaphylactic reactions to chimeric or
humanized antibodies or fusion proteins
- Known hypersensitivity to Chinese hamster ovary cell products or to
any component of the atezolizumab or bevacizumab formulations
- Any treatment for HCC prior to resection or ablation, including
systemic therapy and locoregional therapy such as TACE
- Treatment with a live, attenuated vaccine within 4 weeks prior to Day
1 of Cycle 1, or anticipation of need for such a vaccine during
atezolizumab treatment or within 5 months after the final dose of
atezolizumab
- Treatment with investigational therapy within 4 weeks prior to Day 1
of Cycle 1
- Prior treatment with CD137 agonists or immune checkpoint blockade
therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic
antibodies
- Treatment with systemic immune stimulatory agents within 4 weeks
or 5 drug elimination half-lives prior to Day 1 of Cycle 1
- Treatment with systemic immunosuppressive medication within 2
weeks prior to Day 1 of Cycle 1, or anticipation of need for systemic
immunosuppressive medication during study treatment
- Inadequately controlled arterial hypertension, based on an average
of at least three BP readings at two or more sessions
- History of hypertensive crisis or hypertensive encephalopathy
- Significant vascular disease within 6 months prior to Day 1 of Cycle 1
- History of hemoptysis within 1 month prior to Day 1 of Cycle 1
- Evidence of bleeding diathesis or significant coagulopathy
- Current or recent use of aspirin or current or recent treatment with
dipyramidole, ticlopidine, clopidogrel, and cilostazol
- Current or recent use of full-dose oral or parenteral anticoagulants or
thrombolytic agents for therapeutic purpose
- Core biopsy or other minor surgical procedure, excluding placement
of a vascular access device, within 3 days prior to Day 1 of Cycle 1
- History of GI fistula, GI perforation, or
intra-abdominal abscess within 6 months prior to Day 1 of Cycle 1
- Evidence of abdominal free air that is not explained by paracentesis or
recent surgical procedure
- Serious, non-healing or dehiscing wound, active ulcer, or untreated
bone fracture
- Major surgical procedure within 4 weeks prior to Day 1 of Cycle 1 or
anticipation of need for a major surgical procedure during the study
- History of clinically significant intra-abdominal inflammatory process within
6 months
prior to Day 1 of Cycle 1, including, but not limited to, peptic ulcer
disease, diverticulitis, or colitis
- Chronic daily treatment with a non-steroidal anti-inflammatory drug
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-504303-86-00 |
| EudraCT | EUCTR2019-002491-14-NL |
| ClinicalTrials.gov | NCT04102098 |
| CCMO | NL72323.056.19 |